Mutation of the TGF-beta type II receptor gene and the development of resistance to TGF-beta represent relatively late events in the process of carcinogenesis and may make a key contribution to the transition from late adenoma to frank malignancy. Previously, we reported a correlation between resistance to TGF-beta in human gastric cancer cell lines and gross structural abnormalities of the TGF-beta type II receptor gene. We have also established a correlation between microsatellite instability and TGF-beta RII gene mutations in human gastric carcinoma. A screen of the gastric cancer cell lines included in our previous study has detected microsatellite instability in two cell lines, SNU-1 and - 638. Both cell lines are resistant to TGF-beta and demonstrate undetectable levels of TGF-beta RII transcripts. We have investigated the role of TGF-beta RII in regulating the tumorigenic potential of the human gastric cancer cell line which encodes a truncated, inactive TGF- beta RII protein by introducing the wild-type RII cDNA. Cell expressing wild type TGF-beta RII led to significant increases in TGF-beta RII protein and mRNA. These cells responded to exogenous TGF-beta with reduced proliferation. When transplanted into athymic nude mice, wild- type TGF-beta RII expressing gastric cancer cells showed decreased and delayed tumorigenicity compared with control cells. This study suggests a strong association between the expression of wild-type TGF-beta RII and the degree of malignancy in human gastric cancer cells. promoter.